Reversible, Sexually Dimorphic Sympathetic Aging: Distal Axon Withdrawal Shaped by Prepubertal Gonadal Influences
Year: 2026
Type: preprint
Abstract: Peripheral innervation declines with age, but whether this process is sexually dimorphic and whether it reflects neuronal degeneration or deterioration of nerve-target interactions remain unclear. Using mouse skin as a defined neuroeffector system, we show that sympathetic aging is strongly sexually dimorphic, with greater denervation in aged males. Skin-projecting sympathetic neurons remain intact, indicating that denervation reflects distal axon withdrawal rather than neuronal loss. Nerve-target interactions and the arrector pili muscle niche deteriorate with age, predominantly in males. Aged sympathetic neurons retain NGF responsiveness, and restoring NGF within arrector pili muscles promotes sympathetic reinnervation and hair regeneration in aged males. Genetic and endocrine models show that divergent aging trajectories are associated with gonadal rather than chromosomal sex and are attenuated by early gonadectomy. Together, these findings identify sympathetic aging as a reversible, sexually dimorphic distal axonopathy shaped by the target environment and gonadal influences.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G3298219120, Training Program Bridging Stem Cell Research with Clinical Applications in Regenerative Medicine, 17 alpha-estradiol as a potential protective therapeutic against development of Alzheimer's disease, USC COMPASS: Guiding Undergraduates to Careers in Regenerative Medicine, Sexual Dimorphism in Bladder Cancer, Sex, Chromosomes, and Immunity in Bladder Cancer, USC-Buck Geroscience Training in the Biology of Aging, Deciphering hormonal regulation of neutrophil biology, Training in Developmental Biology, Stem Cells and Regeneration
OpenAlex ID: W7211903142